Nonspecific Stimulation of the Maternal Immune System. II. Effects on Gene Expression in the Fetus

Background: Maternal immune stimulation reduces malformations caused by chemical teratogens. Mechanisms for this effect are not known. Altered expression of regulatory molecules (e.g., transforming growth factor [TGF-β], tumor necrosis factor-a [TNF-α]) has been reported in fetuses from immunostimulated mice, which may affect gene expression. Expression of selected genes that function to control proliferation, differentiation, or apoptosis was evaluated in chemical-exposed fetuses, with or without maternal immunostimulation. Methods: Ethyl carbamate (urethane) was given to pregnant ICR mice on day 10 of gestation to induce cleft palate. Before teratogen administration, the immune system of the female mice was stimulated by footpad injection with Freund's complete adjuvant (FCA) or by intraperitoneal injection with interferon-γ (IFN-γ). Results: Maternal immunostimulation with interferon-y (IFN-γ) decreased severity of the cleft palate lesion caused by urethane, while FCA decreased both incidence and severity of cleft palate. Gestation day 14 fetuses from urethane-exposed mothers displayed decreased expression of cell cycle/apoptotic genes bcl2a, bcl2β, pkCa, and p53 in fetal heads. Immune stimulation with IFN-γ-normalized expression of bcl2α, bcl2β, and pkCa to control levels. Urethane also decreased the ratio of expression of bcla/p53, bclβ/ p53, and pkCα/p53, while maternal injection with IFN-γ restored these expression ratios to control levels. Maternal immunization with FCA also significantly increased bcl2a/p53, bcl2β/p53, and pkCα/p53 gene expression ratios. Conclusions: These results suggest that (1) the maternal immune system may possess heretofore unrecognized regulatory activity in fetal development, and (2) protection against urethane-induced cleft palate may be mediated through maternal immune regulation of fetal gene expression.